EP0069380A1 - 11-Deoxoglycyrrhetinsäurehydrogenmaleinat, Verfahren zu dessen Herstellung und seine Verwendung als Medikament - Google Patents

11-Deoxoglycyrrhetinsäurehydrogenmaleinat, Verfahren zu dessen Herstellung und seine Verwendung als Medikament Download PDF

Info

Publication number
EP0069380A1
EP0069380A1 EP82105994A EP82105994A EP0069380A1 EP 0069380 A1 EP0069380 A1 EP 0069380A1 EP 82105994 A EP82105994 A EP 82105994A EP 82105994 A EP82105994 A EP 82105994A EP 0069380 A1 EP0069380 A1 EP 0069380A1
Authority
EP
European Patent Office
Prior art keywords
compound
salt
hydrogen maleate
pharmaceutical preparation
acid hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP82105994A
Other languages
English (en)
French (fr)
Other versions
EP0069380B1 (de
Inventor
Shigeshi Toyoshima
Hajime Fujimura
Shunsuke Ito
Yasuji Kondo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Maruzen Pharmaceutical Co Ltd
Original Assignee
Maruzen Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Maruzen Pharmaceutical Co Ltd filed Critical Maruzen Pharmaceutical Co Ltd
Priority to AT82105994T priority Critical patent/ATE13523T1/de
Publication of EP0069380A1 publication Critical patent/EP0069380A1/de
Application granted granted Critical
Publication of EP0069380B1 publication Critical patent/EP0069380B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C62/30—Unsaturated compounds
    • C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/593—Dicarboxylic acid esters having only one carbon-to-carbon double bond
    • C07C69/60—Maleic acid esters; Fumaric acid esters

Definitions

  • This invention relates to a novel 11-deoxo- glycyrrhetinic acid derivative, and more specifically, to 11-deoxoglycyrrhetinic acid hydrogen maleate of the following formula a process for its production, and its use as a medicine, especially as an antiulcer agent, an anti-inflammatory agent, or a celluloar immunity activator.
  • glycyrrhizin its aglycone 18 ⁇ -glycyrrhetic acid, and its derivatives.
  • a typical example is glycyrrhetinic acid hydrogen succinate sodium salt, also known as carbenoxolone sodium, which is a highly water-soluble glycyrrhetinic acid derivative (see British Patent No. 843,133) and is actually used as an agent for treating gastric ulcer.
  • glycyrrhetinic acid and its derivatives have an aldosterone (DCA)-like activity and promote sodium retention and potassium excretion, which are likely to induce serious side-effects such as edema, a decrease in serum potassium level, a rise in blood pressure and myopathy.
  • DCA aldosterone
  • the present inventors synthesized many derivatives of 11-deoxoglycyrrhetinic acid, and examined their biological and pharmacological activities. Consequently, they have found that the compound of formula (I) given above, i.e. a semiester formed between 11-deoxoglycyrrhetinic acid and maleic acid, has very good anti-ulcer, anti-inflammatory and delayed-type cellular immunity activating actions without any of the side-effects mentioned above, and therefore, is very suitable as a safe medicine.
  • 11-deoxoglycyrrhetinic acid hydrogen maleate provided by this invention has two carboxyl groups, and can exist in the form of a salt.
  • the salt include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and an aluminum salt.
  • pharmaceutically acceptable salts such as the sodium, potassium and aluminum salts, are preferred.
  • the compound of formula (I) provided by this invention can be produced by reacting 11-deoxoglycyrrhetinic acid of the following formula with an ester-forming reactive derivative of maleic acid, such as maleic anhydride.
  • the above esterification reaction can usually be carried out in an inert organic solvent such as an ether (e.g., dixoane, tetrahydrofuran, etc.), or an aromatic hydrocarbon (e.g., benzene, toluene, xylene, etc.).
  • the reaction temperature is not critical, and can be varied depending upon the type of the ester-forming reactive derivative of maleic acid.
  • maleic anhydride is used, the reaction temperature is generally about 100°C to the refluxing temperature of the reaction mixture, preferably the refluxing temperature of the reaction mixture or temperatures near it.
  • the reaction time which may vary depending upon the reaction temperature used, is generally about 5 to about 40 hours.
  • the amount of maleic anhydride to be used relative to the compound of formula (II) is neither critical.
  • the suitable amount of maleic anhydride is 1.5 to 2.0 moles, preferably 2.0 to 3.0 moles, per mole of the compound of formula (II).
  • the compound of formula (I) can be separated from the reaction mixture, and purified, by methods known per se, such as recrystallization and chromatography.
  • the compound of formula (I) so obtained may be converted to its salt by treating it with sodium hydroxide, potassium hydroxide, aluminum chloride, etc. in accordance with methods known per se.
  • the 11-deoxoglycyrrhetinic acid of formula (II) used as a starting material in the above process is a known compound, and can be produced, for example, by dissolving glycyrrhetinic acid in a suitable solvent such as acetic acid, methanol, ethanol, dioxane, or tetrahydrofuran, and reducing it.
  • a suitable solvent such as acetic acid, methanol, ethanol, dioxane, or tetrahydrofuran
  • the reduction may be carried out by a conventional catalystic reducing method using hydrogen in the presence of a catalyst, for example a metal such as platinum or palladium or its oxide.
  • the compound of formula (I) and its aalts provided by this invention are characterized by having excellent antiulcer, antiinflammatory and delayed-type cellular immunity activating actions and extremely low toxicity (particularly in oral administration) and being free from side-effects (e.g., edema, a decrease in serum potassium level, a rise in blood pressure, a myopathy, etc.). Furthermore, the compound of formula (I) and its salts have antitumor activity. Animal experiments shown below can demonstrate the superior biological activities and the low toxicity of the compounds of this invention.
  • Pylorus ligating method (Shay's ulcer):-Rats, 10 per group, were used, and allowed to fast for 48 hours in separate cages while giving them only water.
  • Pentobarbital sodium was injected intraperitoneally to the rats in a dose of 5 mg per rat. Under anesthesia, the abdomen of each rat was incised, and the portion leading from the pylorus to the duodenum was ligated. Then, the abdomen was sutured. The rats were then left for 19 hours without giving them food and water. Then, under ether anesthesia, the rats were killed by removing the spinal cord. The stomach was excised, and the amount of the gastric juice was measured. The stomach was then cut open along its greater curvature, and placed on a cork plate. The area of an ulcer generated at the anterior stomach was measured by means of an Olympus stereoscope (magnification lOX), and the ulcer index was calculated on the basis of the following criteria.
  • test compound of the invention was injected immediately after the ligation, or orally administered 30 minutes before the ligation.
  • physiological saline was given at a rate of 1 ml per 100 g of body weight.
  • Acetic acid-induced ulcer 5 or 10 per group, were used. After they were anesthetized with pentobarbital sodium, the abdomen was incised, and 0.05 ml of 10% acetic acid was injected into the mucous membrane from the serous layer at the boundary portion in the anterior wall between the body of the stomach and the pylorus part. The abdomen was then sutured.
  • Each of the test drugs shown in Table 2 was intraperitoneally or orally administered once a day for 10 consecutive days beginning with the second day after the above operation. On the 15th day after the operation, the stomach was excised and 12 ml of 1% formalin was injected into it. Then, the stomach was dipped in 1% formalin for 10 minutes, and cut open along the greater curvature. The area of an ulcer generated was measured, and the ulcer index was calculated on the basis of the following standard.
  • tissue respiration activator used was a calf's blood extract preparation administered at a rate of 0.5 ml per 100 g of body weight (this applies to all tissue respiration activators appearing hereinafter).
  • Soress ulcer -Rats, 5 per group, were used. They were put in wire gauze stress cages (made by Natsume Seisakusho) in an upstanding position. The cages were put in a water bath kept constantly at 23°C, and the rats were immersed to a level of the sternal projection. Each of the drugs shown in Table 3 was administered to the rats intraperitoneally or orally 15 minutes before water immersion. Seven hours after the aministration, the rats were knocked out to death. The stomach was excised, and the length of a stress ulcer (erosion) was measured. The results are shown in Table 3.
  • Each of the test drugs shown in Table 4 was administered to the rats intraperitoneally or orally 10 minutes before the administration of indomethacin. The results are shown in Table 4.
  • mice Female Donryu-strain rats (body weight 170 ⁇ 10 g), 10 per group, were used in an anti-inflammatory activity test.
  • the sodium salt of the compound of formula (I) was used as the compound of this invention. It was uniformly mixed with macrogol (a mixture of equal amounts of polyethylene glycol 400 and polyethylene glycol 4000) to form ointments having the varying concentrations as shown in Table 5.
  • 0.05 ml of a 1% aqueous carrageenan solution as an inflammation-inducing agent was inoculated subcutaneously in the foot pad of the right hind legs of each of the rats. Immediately after the inoculation, the pad was wrapped with a gauze (3 x 3 cm) coated with each of the ointments. The volume of the foot was measured before the inoculation of the inflammation-inducing agent and 3 hours after the inoculation. The percent edema and percent inhibition at 3 hours after the inoculation were calculated in accordance with the following equations.
  • mice 10 per group, were used.
  • Sheep red blood cells (1.0 x 10 7 ) were subcutaneously inoculated in the right foot pad of each mouse. The day of inoculation was taken as day 0, and on the same day, the sodium salt of the compound of formula (I) was administered to the mice intraperitoneally or orally.
  • sheep red blood cells (1.0 x 10 7 ) were subcutaneously inoculated in the left foot pad of each mouse, and on day 8, the thickness of each foot pad was measured. The results are shown in Table 6.
  • the compound of this invention (the sodium salt of the compound of formula (I)) was administered to rats, and the rats were observed for 7 days.
  • the LD 50 value was calculated by the method of Reed and Muench. It was found that the LD 50 of the compound of this invention was more than 6000 mg/kg in oral administration, 67.8 mg/kg in intraperitoneal administration, 54.2 mg/kg in intravenous injection, and 98.3 mg/kg in subcutaneous injection.
  • the compound of formula (1) or its salt provided by this invention has excellent antiulcer, anti-inflammatory and delayed-type cellular immunity activating actions and low toxicity, it can be used as an antiulcer agent, an anti-inflammatory agent or a cellular immunity activator for the treatment of peptic ulcer (particularly, gastric ulcer) and inflammation in man and other animals, and/or activating the cellular immunity of these animals.
  • the 11-deoxoglycyrrhetinic acid hydrogen maleate of formula (I) or its salt provided by this invention can be administered singly to man and other animals as a medicament. Generally, however, it is administered as a pharmaceutical preparation comprising a mixture of such a compound with a pharmaceutically compatible inert organic or inorganic diluent or carrier.
  • useful inert diluents or carriers include water, gelatin, gum arabic, lactose, starch and its derivatives, cellulose and its derivatives, magnesium stearate, vegetable oils, polyalkylene glycols, Vaseline, talc, aluminum silicate, aluminum magnesium silicate, calcium carbonate, polyvinyl pyrrolidone, lactose, and crystalline cellulose.
  • the pharmaceutical preparation may be formed into any desired unit dosage form suitable for oral, parenteral or topical application.
  • it may be in the form of a solid preparation such as a powder, granules, tablets (including sugar-coated ones), capsules and a suppository, a liquid preparation such as an injectable, a solution, a suspension or an emulsion, or a semi-solid preparation such as an ointment and cream.
  • these preparations may be sterilized, and/or may contain other pharmaceutical adjuvants such as antiseptics, stabilizers, wetting agents, emulsifiers, salts for changing osmotic pressures, and buffers. They may further include other therapeutically valuable agents.
  • the compound of formula (I) or its salt is to be used as an injecting preparation, it may be converted to a dried (or lyophilized) powder, and then diluted with a diluent such as water or physiological saline.
  • the above preparations may contain generally 0.1 to 95% by weight of the compound of formula (I) or its salt although the concentration may vary depending upon their form.
  • concentration of the compound of formula (I) or its salt may be 0.2 to 0.4% by weight for injectables, 20 to 50% by weight for solid oral preparations, and 0.2 to 1% by weight for topical coating preparations.
  • the compound of formula (I) or its salt may be administered orally, parenterally or topically. Usually, it is advantageously administered through the oral route.
  • the dosage of the compound of formula (I) or its salt may be varied depending upon the type, age, body weight, etc. of an animal to which it is to be administered. For example, for each human adult per day, it is about 10 to about 20 mg for administration by injection, and about 50 to about 500 mg for oral administration. For topical application, it may suitably be administered as an ointment or cream containing 0.2 to 1.0% of the active ingredient.
  • the daily dose mentioned above may be a single daily dose, or may be divided into several dosages.
  • the aforesaid dose ranges are tentative standards and may be varied below or above the given ranges depending upon the condition, age and body weight of the patient, the physician's judgement, etc.
  • Ethanol 100 ml was added to 50 g of 11- deoxoglycyrrhetinic acid hydrogen maleate, and with stirring, a 10% aqueous solution of sodium hydroxide was added dropwise for neutralization. The mixture was filtered, and the filtrate was concentrated under reduced pressure and dried to give a sodium salt of 11-deoxo- glycyrrhetinic acid hydrogen maleate.
  • Ethanol 100 ml was added to 50 g of 11-deoxo- glycyrrhetinic acid hydrogen maleate, and with stirring, a 10% aqueous solution of sodium hydroxide was added dropwise for neutralization. The mixture was filtered, and to the filtrate was added dropwise a solution of 14.4 g of aluminum chloride (AlCl 3 ⁇ 6H 3 O) in 20 ml of water with stirring. The precipitated crystals were collected by filtration, washed with water until no chlorine ion was detected. Then, they were dried to give an aluminum salt of 11-deoxoglycyrrhetinic acid hydrogen maleate.
  • the above ingredients were uniformly mixed, and reduced to a powder or fine particles in a customary manner.
  • the above ingredients were uniformly mixed, compressed, pulverized, and then sieved to form granules.
  • Example B 99 Parts of the granules obtained in Example B were mixed with I part of magnesium stearate. The mixture was compression-molded to form tablets each having a diameter of 7 mm.
  • the above ingredients were mixed and dissolved.
  • the solution was filtered, and then filled in ampoules for injection.
  • the ampoules were sterilized to form an injecting preparation.
  • the sodium salt of the compound of formula (I) of this invention was dissolved in purified water, and mixed well with a hydrophilic ointment of the following recipe described in the Pharmacopoeia of Japan to prepare a hydrophilic ointment containing 0.5 to 2.0% of the compound of the invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP82105994A 1981-07-06 1982-07-05 11-Deoxoglycyrrhetinsäurehydrogenmaleinat, Verfahren zu dessen Herstellung und seine Verwendung als Medikament Expired EP0069380B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT82105994T ATE13523T1 (de) 1981-07-06 1982-07-05 11-deoxoglycyrrhetinsaeurehydrogenmaleinat, verfahren zu dessen herstellung und seine verwendung als medikament.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP104406/81 1981-07-06
JP56104406A JPS588044A (ja) 1981-07-06 1981-07-06 １１−デオキソグリチルレチン酸水素マレ−ト及びそれを有効成分とする医薬

Publications (2)

Publication Number Publication Date
EP0069380A1 true EP0069380A1 (de) 1983-01-12
EP0069380B1 EP0069380B1 (de) 1985-05-29

Family

ID=14379827

Family Applications (1)

Application Number Title Priority Date Filing Date
EP82105994A Expired EP0069380B1 (de) 1981-07-06 1982-07-05 11-Deoxoglycyrrhetinsäurehydrogenmaleinat, Verfahren zu dessen Herstellung und seine Verwendung als Medikament

Country Status (5)

Country Link
US (1) US4448788A (de)
EP (1) EP0069380B1 (de)
JP (1) JPS588044A (de)
AT (1) ATE13523T1 (de)
DE (1) DE3263882D1 (de)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3322617A1 (de) * 1982-06-30 1984-01-05 Biorex Laboratories Ltd., London Pharmazeutische zusammensetzungen
GB2140809A (en) * 1983-06-01 1984-12-05 Biorex Laboratories Ltd New derivatives of glycyrrhetinic acid
EP0272478A1 (de) * 1986-11-28 1988-06-29 Sanwa Kagaku Kenkyusho Co., Ltd. Glyzirrhetinsäure-Derivate und ihre Anwendung
EP0691813A1 (de) * 1992-09-10 1996-01-17 Glycomed Incorporated Derivate von triterpen-säuren als inhibitoren der zelladhäsions-moleküle elam-1(e-selectin) und lecam-1(l-selectin)
EP0693079A1 (de) * 1993-04-16 1996-01-24 Glycomed Incorporated Derivate von triterpenoid-säuren und ihre verwendung
WO2007105015A2 (en) * 2006-03-10 2007-09-20 York Pharma Plc DERIVATIVES OF 18ß-GLYCYRRHETINIC ACID

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1215626B (it) * 1982-07-26 1990-02-22 Isf Spa Derivato dell'acido ursolico farmacologicamente attivo.
JPS6058973A (ja) * 1983-09-13 1985-04-05 Mitsubishi Yuka Yakuhin Kk γ−プチロラクトン誘導体及びそれを有効成分とする免疫調節剤
US4987151A (en) * 1989-06-19 1991-01-22 The Trustees Of Columbia University In The City Of New York Triterpene derivatives cholesterol acyltransferase inhibitors and methods of using same
GB0105772D0 (en) * 2001-03-08 2001-04-25 Sterix Ltd Use
CN101899081B (zh) * 2009-05-31 2012-09-05 江苏正大天晴药业股份有限公司 甘草次酸酯类衍生物合成方法以及脱氧甘草次酸酯化合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2209391B2 (de) * 1971-08-06 1974-02-21 I.S.F. S.P.A., Trezzano Sul Naviglio, Mailand (Italien) Verfahren zur Herstellung der 3-0-(beta-carboxypropionyty-lS-beta-Glycyrrhetinsäure
GB1475075A (en) * 1974-09-11 1977-06-01 Biorex Laboratories Ltd Derivatives of glycyrrhetinic and oleanolic acids

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1435622A (en) * 1973-11-07 1976-05-12 Biorex Laboratories Ltd Erythrodiol derivatives
GB1476053A (en) * 1975-02-07 1977-06-10 Biorex Laboratories Ltd Glycyrrhetinic acid derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2209391B2 (de) * 1971-08-06 1974-02-21 I.S.F. S.P.A., Trezzano Sul Naviglio, Mailand (Italien) Verfahren zur Herstellung der 3-0-(beta-carboxypropionyty-lS-beta-Glycyrrhetinsäure
GB1475075A (en) * 1974-09-11 1977-06-01 Biorex Laboratories Ltd Derivatives of glycyrrhetinic and oleanolic acids

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 94, no. 1, 5 January 1981, Columbus, Ohio, (USA) L. CATTEL et al.: "Biosynthesis of Beta-amyrin. Part I. The chemical synthesis of 20alpha-and 20Beta-homo-Beta-amyrins" page 388, columns 1, 2, abstract no. 4135m; & J. Chem. Res., Synop. vol. 2, 1980, pages 58 to 59 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3322617A1 (de) * 1982-06-30 1984-01-05 Biorex Laboratories Ltd., London Pharmazeutische zusammensetzungen
GB2140809A (en) * 1983-06-01 1984-12-05 Biorex Laboratories Ltd New derivatives of glycyrrhetinic acid
EP0272478A1 (de) * 1986-11-28 1988-06-29 Sanwa Kagaku Kenkyusho Co., Ltd. Glyzirrhetinsäure-Derivate und ihre Anwendung
EP0691813A1 (de) * 1992-09-10 1996-01-17 Glycomed Incorporated Derivate von triterpen-säuren als inhibitoren der zelladhäsions-moleküle elam-1(e-selectin) und lecam-1(l-selectin)
EP0691813A4 (de) * 1992-09-10 1996-08-07 Glycomed Inc Derivate von triterpen-säuren als inhibitoren der zelladhäsions-moleküle elam-1(e-selectin) und lecam-1(l-selectin)
EP0693079A1 (de) * 1993-04-16 1996-01-24 Glycomed Incorporated Derivate von triterpenoid-säuren und ihre verwendung
EP0693079A4 (de) * 1993-04-16 1996-08-07 Glycomed Inc Derivate von triterpenoid-säuren und ihre verwendung
WO2007105015A2 (en) * 2006-03-10 2007-09-20 York Pharma Plc DERIVATIVES OF 18ß-GLYCYRRHETINIC ACID
WO2007105015A3 (en) * 2006-03-10 2008-03-27 York Pharma Plc DERIVATIVES OF 18ß-GLYCYRRHETINIC ACID

Also Published As

Publication number Publication date
JPS588044A (ja) 1983-01-18
ATE13523T1 (de) 1985-06-15
JPH0148254B2 (de) 1989-10-18
DE3263882D1 (en) 1985-07-04
EP0069380B1 (de) 1985-05-29
US4448788A (en) 1984-05-15

Similar Documents

Publication Publication Date Title
JP2762522B2 (ja) 血管新生阻害剤
US4066678A (en) 3-trihydroxygermyl propionic acid and its salts and a process for the production thereof
CA1253803A (en) Buccal and nasal compositions containing iron complexes of 3-hydroxy-4-pyrones
EP0069380B1 (de) 11-Deoxoglycyrrhetinsäurehydrogenmaleinat, Verfahren zu dessen Herstellung und seine Verwendung als Medikament
KR100424503B1 (ko) 암전이억제제
EP0339484B1 (de) 4-Chinolincarbonsäure-Derivate, brauchbar zur Behandlung von Haut- und Muco-epithelial-Gewebekrankheiten
AU613890B2 (en) 4-thiazolidinecarboxylic acid derivative, its preparation and pharmaceutical compositions containing it
US5552389A (en) Suppressory compositions against hepatic metastases of tumors
JPS61176585A (ja) ラブダン誘導体の製法
US5506264A (en) Zinc tranexamate compounds
HU210069A9 (en) Oral gallium complexes
JPH03503162A (ja) 化学療法における毒性特性の改良
US3870792A (en) Certain dihydrophthalizines for treating hemorrhage and thrombosis
JP2000302762A (ja) 放射線および化学療法における感受性増強剤であるグリシジアゾール金属塩、並びにそれらの製造方法および使用
JPS604172A (ja) カルノシン水酸化亜鉛塩およびその製造法
SE455420B (sv) Anvendning av 4-fenyl-4-oxo-butensyraderivat for framstellning av ett lekemedel for behandling av magakommor och gastroduodenala akommor i samband med hyperaciditet
EP0623623B1 (de) Komplex von 2-aminoäthansulfonsäure und zink
US4867737A (en) Derivatives of 4-phenyl-4-oxo-2-butenoic acid their preparation process, their use as medicaments and compositions containing them
US4016288A (en) Compositions and method of treating hypertension
US3574852A (en) Treating depression with the n-oxide of n-(3' - dimethylamino propyl)-iminodibenzyl
JPS62294616A (ja) 抗真菌用薬剤
US5489609A (en) 2-aminoethanesulfonic acid zinc complex compound
US4472424A (en) Esters of 2-thenoylmercaptopropionylglycine with substituted hydroxybenzenes, process for their preparation and pharmaceutical compositions containing same
US3790676A (en) Preventing pain,fever and inflammation with cyclic hydroxy sulfoxides
US3560617A (en) Pharmaceutical composition containing 3-butylamino - 4 - chloro-5-sulphamylbenzoic acids and salts thereof for the treatment of oedematous conditions and hypertension

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17P Request for examination filed

Effective date: 19830406

ITF It: translation for a ep patent filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19850529

REF Corresponds to:

Ref document number: 13523

Country of ref document: AT

Date of ref document: 19850615

Kind code of ref document: T

REF Corresponds to:

Ref document number: 3263882

Country of ref document: DE

Date of ref document: 19850704

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Effective date: 19850705

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19850706

ET Fr: translation filed
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19850731

Ref country code: LI

Effective date: 19850731

Ref country code: CH

Effective date: 19850731

Ref country code: BE

Effective date: 19850731

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
BERE Be: lapsed

Owner name: MARUZEN PHARMACEUTICAL CO. LTD

Effective date: 19850731

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19860328

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19860402

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

26N No opposition filed
GBPC Gb: european patent ceased through non-payment of renewal fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19881121

EUG Se: european patent has lapsed

Ref document number: 82105994.6

Effective date: 19860730